Abstract
Simple SummaryIn recent years, the therapeutic armamentarium of mccRCC has changed dramatically with the emergence of targeted therapy and immune checkpoint inhibitors, used alone or as a combination. However, mccRCC still have a poor prognosis and a significant portion of patients experience primary or secondary resistance. The tumor microenvironment plays a major role in promoting tumor resistances. This review aims (i) to provide an overview of the components of the RCC tumor microenvironment, (ii) to discuss their role in disease progression and resistance to ICI, (iii) to highlight the current and future ICI predictive biomarkers assessed in mcccRCC.Renal cell carcinoma (RCC) is the seventh most frequently diagnosed malignancy with an increasing incidence in developed countries. Despite a greater understanding of the cancer biology, which has led to an increase of therapeutic options, metastatic clear cell renal cell carcinoma (mccRCC) still have a poor prognosis with a median five-years survival rate lower than 10%. The standard of care for mccRCC has changed dramatically over the past decades with the emergence of new treatments: anti-VEGFR tyrosine kinase inhibitors, mTOR Inhibitors and immune checkpoint inhibitors (ICI) such as anti-Programmed cell-Death 1 (PD-1) and anti-anti-Programmed Death Ligand-1 (PD-L1) used as monotherapy or as a combination with anti CTLA-4 or anti angiogenic therapies. In the face of these rising therapeutic options, the question of the therapeutic sequences is crucial. Predictive biomarkers are urgently required to provide a personalized treatment for each patient. Disappointingly, the usual ICI biomarkers, PD-L1 expression and Tumor Mutational Burden, approved in melanoma or non-small cell lung cancer (NSCLC) have failed to distinguish good and poor mccRCC responders to ICI. The tumor microenvironment is known to be involved in ICI response. Innovative technologies can be used to explore the immune contexture of tumors and to find predictive and prognostic biomarkers. Recent comprehensive molecular characterization of RCC has led to the development of robust genomic signatures, which could be used as predictive biomarkers. This review will provide an overview of the components of the RCC tumor microenvironment and discuss their role in disease progression and resistance to ICI. We will then highlight the current and future ICI predictive biomarkers assessed in mccRCC with a major focus on immunohistochemistry markers and genomic signatures.
Highlights
Kidney cancer accounts for 3 to 5% of all malignancies, with an increasing incidence in developed countries
During the 2000s, anti-VEGFR tyrosine kinase inhibitor (TKI) and mTOR inhibitors emerged as the new standards of care for metastatic clear cell renal cell carcinoma
In a recent study focusing on clear cell renal cell carcinoma (ccRCC), a favorable immunoscore was associated with improved survival outcomes [17]
Summary
Kidney cancer accounts for 3 to 5% of all malignancies, with an increasing incidence in developed countries. During the 2000s, anti-VEGFR TKI and mTOR inhibitors emerged as the new standards of care for metastatic clear cell renal cell carcinoma (mccRCC). Were approved for first-line MSKCC intermediate and poor risk mccRCC patients and after anti-VEGFR TKI failure. Compared with the placebo or interferon, sunitinib and pazopanib provided a survival benefit with a median overall survival of 29.3 and 28.4 months, respectively [8]. In the last few years, the standard of care for mccRCC has changed dramatically with the emergence of immune checkpoint inhibitors (ICI) anti-Programmed cell-Death 1 (PD-1). ICI combinations have changed the prognostic of mccRCC with impressive overall response rates (ORR) We will make a particular focus on the potentiality of the TME to induce resistance to ICI and highlight the current and future ICI predictive biomarkers assessed in mccRCC
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